Sphingomyelin synthase

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SMSr-ceramide
Fig1c.png
The cryo-EM structure of human sphingomyelin synthase-related protein in complex with ceramide. PDB 8IJQ
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EC no. 2.7.8.27
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In enzymology, a sphingomyelin synthase (EC 2.7.8.27) is an enzyme that catalyzes the chemical reaction

a ceramide + a phosphatidylcholine a sphingomyelin + a 1,2-diacyl-sn-glycerol

or the reaction using phosphatidylethanolamine instead of phosphatidylcholine to generate ceramide phosphoethanolamine (CPE), a sphingomyelin analog rich in invertebrates, such as insects.

Thus, the two substrates of this enzyme are ceramide and phosphatidylcholine, whereas its two products are sphingomyelin and 1,2-diacyl-sn-glycerol.

This enzyme belongs to the family of transferases, specifically those transferring non-standard substituted phosphate groups. The systematic name of this enzyme class is ceramide:phosphatidylcholine cholinephosphotransferase. Other names in common use include SM synthase, SMS1, and SMS2. SM synthase family also includes the enzyme catalyzing CPE synthesis, named SMSr (SMS-related).

Structure of SM synthases

The high sequence identities shared among the three members of the Sphingomyelin Synthase (SMS) family have intrigued researchers for years. Recent cryo-electron microscopic studies have unveiled a fascinating hexameric organization specifically for SMSr, [1] while biochemical investigations have highlighted the formation of stable dimers by SMS1 and SMS2. [2] Within this hexameric structure, each monomeric unit of SMSr functions as an independent catalytic entity, characterized by six transmembrane helices.

The structural analysis has revealed the presence of a sizable chamber within the helical bundle of SMSr. This chamber serves as the site for catalytic activity, with researchers pinpointing a catalytic pentad, denoted as E-H/D-H-D, strategically positioned at the interface between the lipophilic and hydrophilic segments of the reaction chamber. Furthermore, the elucidation of SMSr's catalytic mechanism has uncovered an intricate two-step synthesis process for SM synthesis. Initially, phosphoethanolamine (or phosphatidylcholine in case of SMS1/2) is hydrolyzed from phosphatidylethanolamine (PE-PLC hydrolysis), followed by the subsequent transfer of the phosphoethanolamine moiety to ceramide.

Related Research Articles

<span class="mw-page-title-main">Sphingomyelin</span> Class of chemical compounds

Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids. In humans, SPH represents ~85% of all sphingolipids, and typically make up 10–20 mol % of plasma membrane lipids.

<span class="mw-page-title-main">Ceramide</span> Family of waxy lipid molecules

Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely supporting structural elements, ceramide can participate in a variety of cellular signaling: examples include regulating differentiation, proliferation, and programmed cell death (PCD) of cells.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Sphingomyelin phosphodiesterase</span> Class of enzymes

Sphingomyelin phosphodiesterase is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. SMase is a member of the DNase I superfamily of enzymes and is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide. The activation of SMase has been suggested as a major route for the production of ceramide in response to cellular stresses.

<span class="mw-page-title-main">1-Aminocyclopropane-1-carboxylate synthase</span> Class of enzymes

The enzyme aminocyclopropane-1-carboxylic acid synthase catalyzes the synthesis of 1-Aminocyclopropane-1-carboxylic acid (ACC), a precursor for ethylene, from S-Adenosyl methionine, an intermediate in the Yang cycle and activated methyl cycle and a useful molecule for methyl transfer:

The enzyme glycosylphosphatidylinositol diacylglycerol-lyase catalyzes the reaction

<span class="mw-page-title-main">Phosphatidate phosphatase</span>

The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol:

In enzymology, sphingosine N-acyltransferases (ceramide synthases (CerS), EC 2.3.1.24) are enzymes that catalyze the chemical reaction of synthesis of ceramide:

In enzymology, a digalactosyldiacylglycerol synthase is an enzyme that catalyzes the chemical reaction

In enzymology, a galactolipid galactosyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a monogalactosyldiacylglycerol synthase is an enzyme that catalyzes the chemical reaction

In enzymology, a CDP-diacylglycerol—serine O-phosphatidyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a ceramide kinase, also abbreviated as CERK, is an enzyme that catalyzes the chemical reaction:

In enzymology, a phosphatidylcholine synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">UGCG</span> Protein-coding gene in the species Homo sapiens

Ceramide glucosyltransferase is an enzyme that in humans is encoded by the UGCG gene.

<span class="mw-page-title-main">SGMS1</span> Protein-coding gene in the species Homo sapiens

Phosphatidylcholine:ceramide cholinephosphotransferase 1 is an enzyme that in humans is encoded by the SGMS1 gene.

<span class="mw-page-title-main">1-Lysophosphatidylcholine</span>

1-Lysophosphatidylcholines are a class of phospholipids that are intermediates in the metabolism of lipids. They result from the hydrolysis of an acyl group from the sn-1 position of phosphatidylcholine. They are also called 2-acyl-sn-glycero-3-phosphocholines. The synthesis of phosphatidylcholines with specific fatty acids occurs through the synthesis of 1-lysoPC. The formation of various other lipids generates 1-lysoPC as a by-product.

In enzymology, a ceramide phosphoethanolamine synthase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Ceramide synthase 1</span> Protein-coding gene in the species Homo sapiens

Ceramide synthase 1 also known as LAG1 longevity assurance homolog 1 is an enzyme that in humans is encoded by the CERS1 gene.

Ceramide synthase 5 (CerS5) is the enzyme encoded in humans by the CERS5 gene.

References

  1. Hu K, Zhang Q, Chen Y, Yang J, Xia Y, Rao B, et al. (2024). "Cryo-EM structure of human sphingomyelin synthase and its mechanistic implications for sphingomyelin synthesis". Nat Struct Mol Biol: 1–12. doi:10.1038/s41594-024-01237-2.
  2. Hayashi Y, Nemoto-Sasaki Y, Matsumoto N, Tanikawa T, Oka S, Tanaka Y, et al. (January 2017). "Carboxyl-terminal Tail-mediated Homodimerizations of Sphingomyelin Synthases Are Responsible for Efficient Export from the Endoplasmic Reticulum". Journal of Biological Chemistry. 292 (3): 1122–1141. doi: 10.1074/jbc.M116.746602 . PMC   5247646 . PMID   27927984.